THE GENETICS OF MOVEMENT DISORDERS

Most individuals diagnosed with a movement disorder ask themselves and their doctors "Why did I develop these symptoms?" Some people know of other family members with the same symptoms as them, suggesting that the cause of their disease is genetic (hereditary). Others do not have a family history of a movement disorder but are told by their doctor that their symptoms are consistent with a genetic condition. We used to categorize diseases as simply being "genetic" or "non-genetic/environmental". It has now become apparent that even diseases that do not run in families, and appear to be 'sporadic', may be caused by subtle genetic influences. It is now commonly accepted that most of the 'sporadic' common diseases such as heart disease, cancer and diabetes are caused by subtle genetic factors (such as those factors that determine how the body regulates sugar, responds to infection etc) together with environmental affects that can be modulated (including diet, exercise, smoking, pollutant exposure). We are now learning that this applies also to some movement disorders such as Parkinson's disease and the adult-onset focal dystonias.

The recent advances in genetic research are now, for the first time, directly benefiting individuals and their families with genetic conditions. For some diseases, genetic testing is available to confirm a genetic diagnosis, for others, testing is not yet available, but opportunities exist for individuals and their families to be part of the research effort to understand the cause of movement disorders. As movement disorders specialists, we are continuously expanding our research efforts to keep pace with new clinical and genetic findings and to ensure, in the future, that we can provide answers to individuals who ask "Why did I develop this disease?"

The information presented here aims to help individuals wishing to learn more information about the genetics of movement disorders, and to help them navigate through terms such as 'genetic testing', 'genetic counseling' and 'genetic research.'

Why is it important to research family history of disease?

It is common practice for a neurologist to ask an individual with symptoms of a neurological condition whether other family members are also affected with the same or related symptoms. It is therefore useful to know or investigate family history of disease including symptoms, ages of onset, causes and ages of death in family members including siblings, parents, grandparents, uncles, aunts and first cousins. Such knowledge may provide the key to a diagnosis. If a pattern of symptoms or a family history suggests a genetic disease, a referral for genetic counseling and testing may be required (see below for information about genetic counseling).

What is genetic testing?

Over 40 types of movement disorders are caused by a genetic change in a single gene. They are either manifested by autosomal recessive inheritance (both parents of the affected individual are unaffected, but carriers of the condition), autosomal dominant inheritance (the affected individual inherited a mutation in a disease-causing gene from one of his/her parents who may or may not also have symptoms of the disease), by mitochondrial inheritance (an affected individual received the mitochondrial genetic change from his/her mother, who may or may not have symptoms of the disease), or X-linked inheritance (an affected son or daughter inherits the disease from his or her unaffected mother - usually sons are more likely to be affected). Researchers have spent many years working with families affected with inherited movement disorders to identify disease-causing genes. Gene identification leads to research that uncovers the frequency and types of genetic changes in a specific gene. If clinically useful, this information can result in the development of a genetic test in a government-approved laboratory, with a high sensitivity and specificity to enable families with an inherited movement disorder to identify, through genetic testing, the cause of their disease.

Genetic DNA testing is available for the following movement disorders:

Table 1: Genetic diseases for which genetic DNA testing is currently available

The genetic cause of movement disorders in table 2 are known, however genetic testing is not widely available for a variety of reasons. For example people with Dopa-Responsive Dystonia (DRD) all have different or 'unique' disease-causing mutations in the GTP cyclohydrolase gene. The gene is also extremely large, which means that in order to find a person's disease-causing mutation, the entire gene has to be sequenced to search for mutations. There are also regions of the gene and types of mutations that are difficult to sequence. In addition only 60% of people with DRD have mutations in GTP cyclohydrolase, suggesting that other genes exist that can cause disease similar to DRD. Genetic testing is available for most of the diseases in Table 2, but on an extremely limited basis due to a variety of complex issues which make testing difficult. As a result, genetic testing for these diseases can be very time-consuming, laborious and costly. However, for some of these diseases, other diagnostic measures such as the presence of specific neurological symptoms or biochemical tests can be used to make a diagnosis.

Condition (Gene name)

Gene Location

Inheritance pattern

Dopa-Responsive dystonia (GTP cyclohydrolase)

14q22.1‑q22.2

Autosomal Dominant

Frontotemporal Dementia with Parkinsonism-17 (FTD-17)

17q21‑q23

Autosomal Dominant

Hyperekplexia (GLRA1)

5q32

Autosomal Dominant

Lafora BODY disease (EPM2A)

6q24

Autosomal Recessive

Lesch Nyhan (HPRT)

Xq26-q27.2

X-linked

Myoclonus Dystonia (DYT11)

7q21‑q31

Autosomal Dominant

Myoclonic Epilepsy of Unverricht and Lundborg (EPM1)

21q22.3

Autosomal Recessive

Neuroacanthocytosis

9q21

Autosomal Recessive

Neuroferritinopathy / Basal Ganglia Disease (FTL)

19q13.3-q13.4

Autosomal dominant

SOD1-Related Amyotrophic Lateral Sclerosis

21q

Autosomal Dominant

Tyrosine Hydroxylase-Deficient DRD

11p15.5

Autosomal Recessive

Wilson Disease (ATB7B)

13q14.3

Autosomal Recessive

Table 2: Genetic diseases for which genetic DNA testing is currently available on a very limited basis